A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.
Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment.
Dimebon, also referred to as dimebolin, and its structurally related analogues have been shown to inhibit the death of brain cells in preclinical models of Alzheimer's disease (AD) (see, for example, Medivation Form 10KSB filed 19 Feb. 2008). Treatment of patients having mild-to-moderate AD in a randomised, double-blind, placebo-controlled study with dimebon is reported as resulting in significant benefits in assessed cognition, as measured in the cognitive subscale of the Alzheimer's disease assessment scale (ADAS-cog) (see Doody et al.). It is suggested that dimebon is safe, well tolerated, and is capable of improving the clinical course of subjects having AD at a mild to moderate level. Further clinical trials are underway for the use of Dimebon against Alzheimer's disease and for Huntington's disease (see Medivation press release 4 Nov. 2009).
Dimebon has also been reported to be an inhibitor of TDP-43 proteinopathy in cellular models of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FLTD-U) (see Yamashita et al.).
Dimebon has the structure shown below, where the atoms in the pyridoindole group are labelled for reference:

A key intermediate in the synthesis of Dimebon and its analogues is [2-(6-methyl-pyridin-3-yl)-ethyl]-p-tolyl-amine (compound (1)). This compound may be prepared from 2-methyl-5-vinylpyridine (2) and p-toluidine (3), as described, for example, in U.S. Pat. No. 3,409,628 (see Example 14):

Compound 1 may be converted to the dimebon analogue 6 having a benzyl substituent at the pyridoindole 2-position:

Similarly, Kost et al. (J. Gen. Chem. USSR 1960, 30, 2538) describe the use of 2-methyl-5-vinylpyridine for the preparation of related tetrahydrocarbazole structures, such as compound 7:

The synthesis proceeds via 2-methyl-5-(2-phenylaminoethyl)pyridine, an analogue of compound 1.
The synthesis of dimebon is described by Kost et al. (Chemistry of Heterocyclic Compounds, 1973, 9, 191). Dimebon, referred to as 9-[2-(2′-methyl-5′-pyridyl)ethyl]-3,6-dimethyl-1,2,3,4-tetrahydro-γ-carboline, is prepared by the direct reaction of 2-methyl-5-vinylpyridine with the carboline (i.e. 3,6-dimethyl-1,2,3,4-tetrahydro-γ-carboline) in the presence of a very strong base, for example sodium ethoxide.
More recently, Ivachtencko et al. (Bioorg. Med. Chem. Lett., 2009, 19, 3183-3187) have synthesised Dimebon and analogues by a similar method, in which the tricyclic ring system (carboline) is formed and reductively aminated with 2-methyl-5-vinylpyridine, in the presence of base and a phase transfer catalyst.
However, 2-methyl-5-vinylpyridine is not available commercially, and must be prepared as required. 2-Methyl-5-vinylpyridine may be obtained from 5-ethyl-2-methylpyridine by oxidation over a heterogeneous catalyst, typically at elevated temperature. However, the use of sustained high temperatures means that this method is not suitable for the large scale production of 2-methyl-5-vinylpyridine.
For example, U.S. Pat. No. 2,611,769 describes the preparation of 2-methyl-5-vinylpyridine from 5-ethyl-2-methylpyridine at temperatures of 600° C. and above. The amount of product obtained is low, around 16%, and requires separation from unreacted starting material.
U.S. Pat. No. 2,716,119 also describes the preparation of 2-methyl-5-vinylpyridine from 5-ethyl-2-methylpyridine. The reaction step is performed at a temperature of around 700° C. and provides around 25 to 40% yield of material depending on the heterogeneous catalyst chosen.
Furthermore, the preparation of compound 1 from 2-methyl-5-ethylpyridine is reported as requiring the use of sodium metal (see, for example, U.S. Pat. No. 3,409,628). The use of this flammable/pyrophoric metal makes this method undesirable for a large scale synthesis.
Given the recently reported benefits of dimebon, there is a need for alternative methods of synthesis that can be reproduced on a large scale and/or provide increased yields of product. In addition, the methods of the invention avoid the need for complex gas phase reactions and pyrophoric reagents. Specialist equipment and procedures are therefore not needed in the present invention, and the overall cost of the synthesis may thereby be reduced.
The present inventors have established an alternative route to the key intermediate that avoids the use of high temperature oxidation and avoids the use of sodium metal.